Rapamycin, or sirolimus, is a macrolide which was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter Island. Although marketed primarily as an immunosuppressant, more recently several additional indications have been reported for this drug. In several of these indications, it would be useful to increase the amount of rapamycin which could be retained in certain cell types.
The use of certain poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymers having a hydrophobe content of 50% or more by weight as pharmaceutical excipients to enhance the uptake of active materials in certain cell types has been described in a number of publications. See, for example, U.S. Pat. No. 5,840,319; U.S. Pat. No. 6,060,518; Alakhov et al., “Hypersensitization of Multidrug Resistant Human Ovarian Carcinoma Cells by Pluronic P85 Block Coploymer”, Bioconjugate Chem. 7, 209-216 (1996); and Batrakova et al., “Anthracycline antibiotics non-covalently incorporated into copolymer micelles: in vivo evaluation of anti-cancer activity”; British Journal of Cancer 74: 1545-1552 (1996). It is believed that this effect is achieved by the inhibition of ABC mediated efflux mechanisms in such cells. See U.S. Pat. No. 6,387,406.
Unfortunately, such hydrophobic block copolymers (also know an poloxamers; sold under the trade name Pluronics) have been found to aggregate in aqueous solutions at physiological temperatures (see U.S. Pat. No. 6,387,406, Example 34). Such aggregation under physiological conditions can be eliminated by blending such hydrophobic poloxamers with certain hydrophilic poloxamers as described in U.S. Pat. No. 6,387,406.
The use of such mixtures of hydrophilic and hydrophobic copolymers has been shown to greatly increase the effectiveness of certain drugs in clinical studies. Thus, Valle et al.; “A phase 2 study of SP1049C, doxorubicin in P-gylcoprotein-targeting pluronics, in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction”; Invest New Drugs; DOI 10.1007/s10637-010-9399-1; published 24 Feb. 2010, describes a Phase II study in which SP 1049C (a composition comprising doxorubicin, hydrophobic Pluronic L61 and hydrophilic Pluronic F127) displayed a response rate of 47% in the evaluable patient population (43% in the ITT formulation). In contrast, Ezdinli et al. “Chemotherapy of Advanced Esophageal Carcinoma”; Cancer 46:2149-2153; 1980; indicates that Adriamycin (a free doxorubicin formulation) elicited a response rate of only 5% when evaluated as a monotherapy in a Phase II study on patients with advanced esophageal cancer (see first full paragraph on page 2152, first column).
Unfortunately, the formulation of hydrophobic and hydrophilic block copolymers employed in the Valle study prepared by mixing Pluronic L61 with Pluronic F127 in an aqueous solution (along with the active material), and freeze drying the mixture to form a waxy pellet does not rapidly dissolve in aqueous solutions. See U.S. Patent Application Publication No. 2007/0196493. Accordingly, such composition requires caution if used in a typical hospital situation, as time must be taken to ensure that the waxy polymeric mixture has fully dissolved in the liquid application medium (typically saline) before administration to patients. U.S. Patent Application Publication No. 2007/0196493 discloses that such waxy mixture will rapidly dissolve in aqueous media if a sugar or similar material, preferably lactose, is incorporated into the polymer matrix by including such material in the aqueous solution which is dried to form the polymeric composition.
While U.S. Patent Application Publication No. 2007/0196493 discloses a mixture which will rapidly dissolve in aqueous media, the waxy nature of such composition makes it unsuitable for use in pills or other similar forms of administration.
Therefore, there is a need for pharmaceutical formulations of rapamycin which can take advantage of the ABC mediated efflux inhibition exhibited by hydrophobic poloxamers (which copolymers are liquids at room temperature), which formulations do not aggregate under physiological conditions, and which are suitable for the production of tablets and other dry forms of application.
Accordingly, it is an object of this invention to provide a rapamycin composition comprising such hydrophobic poloxamers, which composition is in the form of a free flowing, compressible powder.
It is a further object of this invention to provide a method of making the rapamycin composition.